RNA and protein metabolism in the aging brain.

Much work in the molecular neurobiology of aging is still necessarily descriptive, pending more data on the relative contributions of neuron loss vs. neuron atrophy and glial hyperactivity during normal and neuropathological aging. Major loss of neuronal cells is not the rule, even in AD. A working hypothesis holds that increased astrocytic volumes and decreased neuronal volumes are a major factor in age-related neurochemical decreases. Resolution of these questions is needed to understand how regional RNA and protein synthesis change during aging. We have presented alternative mechanisms for changes in gene expression that may be cell specific. The literature, mainly from non-neural tissues, suggests derepression of normally silent genes, possibly in association with DNA demethylation; decreased synthesis of neuronal rRNA due to deletion of rRNA genes; epigenetic changes in hnRNA splicing; reduced turnover rates and the accumulation of nonfunctional proteins. Although global qualitative changes in the inventory of mRNA and proteins are not found in neural tissues at advanced ages, the synthesis and turnover of RNA and protein may be slowed. Impaired protein turnover or catabolism could contribute to the accumulation of NFT and brain amyloid. In sum, several different types of mechanisms appear to be important in RNA and protein metabolism of the brain during aging, but selectivity for brain region and cell type seems to prevail throughout these myriad changes.